In this competing continuation application we propose to extend our investigation of Photodynamic Therapy (PDT). Three of the proposed projects are directed at elucidating the mechanisms by which PDT elicits cellular/tissue response when employed in cancer treatment. Each follows a distinctly different approach to achieve its goals; in subsequent years, each interacts with the other projects. One project deals specifically with non invasive methods to ultimately improve the utility of PDT and one with the extension of fundamental laboratory data into a primary tumor, veterinary clinical trial. Specifically, the projects in this proposal propose to: 1) examine the mechanisms of interaction between PDT and hyperthermia; 2) extend results obtained in laboratory models to spontaneous veterinary tumors; 3) develop a PDT resistant tumor model and subsequently elucidate the mechanisms involved in such resistance; 4) develop non invasive methods to quantitate tissue photosensitizer concentrations; and 5) to establish a quantifiable measure of true tissue photosensitivity to allow the intercomparison of various PDT treatments. This program is a multidisciplinary, multi-institutional investigation aimed at understanding and improving the use of PDT for the treatment of cancer. The inter-relation between the constituent projects enhances the overall effort.